The similarity in virulence factors between 502A and USA300 suggested that these factors were not the cause of the higher mortality with 502A in the mouse studies. Instead, the host immune response may be to blame. In the mouse acute pneumonia model, the enhanced immune response of 502A was characterized by significantly greater concentrations of the inflammatory cytokines CXCL1/KC and interleukin-6, in addition to increased recruitment of dendritic cells and natural killer cells.16 Induction of type I interferon (IFN) is a normal part of the innate immune response to viral and bacterial infection, but IFN has complex effects through multiple pathways and can be detrimental to the host rather than the pathogen.128 Stimulation of mouse lung epithelial cells with 502A induced 100-fold more IFN than stimulation with USA300 (Fig. 4), suggesting that host signaling through IFN may contribute to the increased morbidity and mortality seen with 502A infection of the lung. Strain 502A also appears to activate IFN through a different mechanism than USA300: whereas USA300 activates type I IFN signaling through Toll-like receptor 9,129 502A uses NOD2 (a receptor for peptidoglycan). Furthermore, 502A exhibited increased autolysis, which leads to the release of peptidoglycan from the cell wall, stimulating NOD2 and activating the type I IFN pathway.16 However, live bacteria were required for this IFN response to 502A, so the peptidoglycan of 502A is not inherently more stimulatory than that of USA300; this phenomenon will therefore need to be investigated further. The role of the IFN pathway in morbidity and mortality was confirmed in mice lacking the type I IFN receptor (Ifnar−/− mice): Ifnar−/− mice infected with 502A sustained less lung damage, had lower bacterial burdens in bronchoalveolar lavage fluid, and had lower concentrations of inflammatory cytokines than wild-type mice. Furthermore, in a mortality model, 50% of the Ifnar knockouts survived, whereas only 8% of the wild-type mice survived. These comparative data suggest that 502A may exclude invasive S. aureus strains by stimulating the host immune system while remaining relatively noninvasive itself.
In the face of the severe and persistent disease caused by strain 80/81, the low incidence of 502A disease was a reasonable tradeoff. However, our new understanding of the potential lethality of 502A removes it, in its present form, as an option for future clinical use in newborns. Nonetheless, it makes an excellent model for investigating the host and bacterial mechanisms underlying the interference phenomenon, which could then be used to develop a safer and more targeted intervention for prophylaxis and treatment.
How each strain stimulates the immune response is another crucial question. USA300 and 502A contain very similar virulence factors yet have opposite phenotypes for immunostimulation and invasiveness. We do not know whether any of the virulence factors are necessary for immunostimulation and the exclusion of other strains, or whether it would be possible to separate the specific factors responsible for the protective interference phenotype from those responsible for invasion and pathogenesis. We plan to use genetic approaches—the creation of targeted mutants and screens of mutant libraries—to isolate factors responsible for these phenotypes, or at least to greatly attenuate virulence while retaining the immunostimulation and interference. Because 502A releases more peptidoglycan than USA300, this molecule is an early candidate for examination. WTA, which is covalently attached to peptidoglycan, is another target. A goal is to identify specific molecules that could effectively evoke the interference phenotype while remaining safe for clinical use.
The competition between single strains also needs to be placed in the context of the entire microbial assemblage of the skin and mucous membranes where S. aureus is carried. Interest in the human microbiota and our technical ability to examine its diversity have grown in recent years, and we expect that our understanding of the complex interactions among microbes and their hosts, as well as how bacteria compete with each other, will continue to progress rapidly, providing additional candidate molecules and mechanisms for use in bacterial interference.
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